Since our group has shown that cells of the immune system protect against excess iron, that, in turn, iron and iron binding proteins have important effects on cells of the immune system, that the iron binding protein ferritin is synthesized and secreted by peripheral blood mononuclear cells, and that there are large HLA-associated individual variations in this ferritin secretion, we propose to study the cellular and genetic control of in vitro synthesis and secretion of ferritin by subpopulations of mononuclear cells (MNC). The proposed studies will utilize a modified hemolytic plaque assay with specific antibodies to acidic and basic ferritin isotypes, and "panning" and blocking techniques with monoclonal antibodies to MNC subpopulations and cell-surface determinants, in order: to determine the specific cell types involved in synthesis and secretion of ferritin by either activated on non-activated MNC; to determine the role of matching for HLA determinants in the cell-cell cooperation that occurs; to determine the relationship of particular MNC subpopulations to high" and "low" ferritin seretion; to determine the mechanism by which iron and cell activation induce in vitro ferritin synthesis and secretion; to determine individual variations in the production of ferritin-like factors that may inhibit myelopoiesis; to determine the specific basic and acidic isoferritin components of the ferritin secreted by different individuals; to determine whether quantitative differences in secretion from the cells of different individuals reflect variations in synthesis or variations in secretion only; to determine in studies of families whether or not these variations are inherited in linkage to the HLA complex; to study ferritin secretion in relation to genetic or acquired conditions of iron overload, such as hemochromatosis; and, to determine whether or not individual variations in other in vitro effects of iron on immunefucntion are also HLA associated and correlated with variations in ferritin secretion. These studies will collectively provide important information about the physiological role that cells of the immune system may play in the protection of tissue against potential toxicity from iron and about a mechanism by which genetic variations in the major histocompatibility complex may affect iron metabolism and the immune system itself.